Solution NMR Structure of Apo-Calmodulin in Complex with the IQ Motif of Human Cardiac Sodium Channel NaV1.5

The function of the human voltage-gated sodium channel NaV1.5 is regulated in part by intracellular calcium signals. The ubiquitous calcium sensor protein calmodulin (CaM) is an important part of the complex calcium-sensing apparatus in NaV1.5. CaM interacts with an IQ (isoleucine–glutamine) motif in the large intracellular C-terminal domain of the channel. Using co-expression and co-purification, we have been able to isolate a CaM–IQ motif complex and to determine its high-resolution structure in absence of calcium using multi-dimensional solution NMR. Under these conditions, the NaV1.5 IQ motif interacts with the C-terminal domain (C-lobe) of CaM, with the N-terminal domain remaining free in solution. The structure reveals that the C-lobe adopts a semi-open conformation with the IQ motif bound in a narrow hydrophobic groove. Sequence similarities between voltage-gated sodium channels and voltage-gated calcium channels suggest that the structure of the CaM–NaV1.5 IQ motif complex can serve as a general model for the interaction between CaM and ion channel IQ motifs under low-calcium conditions. The structure also provides insight into the biochemical basis for disease-associated mutations that map to the IQ motif in NaV1.5.

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► The first structure of apo-CaM bound to an ion channel IQ motif is presented.
► Apo-CaM binds the NaV1.5 IQ motif using only its C-terminal domain.
► The CaM C-terminal domain occupies a semi-open conformation.
► This structure serves as a general model for Apo-CaM–ion channel IQ motif complexes.
► Structure suggests that the NaV1.5 long QT syndrome mutant S1904L is defective in CaM binding.